. Epidemiological studies have identified alcohol consumption as an independent risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM). Moreover, both short and long-term ethanol consumption result in glucose intolerance in humans and rats. However, the mechanism(s) for this disruption of glucose homeostasis by ethanol is not well understood. Since adipose and skeletal muscle are major sites for both insulin action and glucose disposal, the applicants have investigated the effects of ethanol on insulin-mediated control of glucose transport in adipocytes and skeletal muscle from rats. Ethanol feeding to rats for four weeks decreased insulin-stimulated glucose uptake in adipocytes and soleus, a red oxidative muscle, but had no effect on uptake in the epitrochlearis, a white glycolytic muscle. Decreased uptake in the adipocyte was associated with an impairment in translocation of GLUT4 from intracellular vesicles to the plasma membrane. Total GLUT4 protein was also reduced after ethanol feeding; as in other model systems, decreased GLUT4 was associated with an increase in G alpha s and cAMP production in the adipocyte. The major goals of this proposal will be to determine whether ethanol impairs insulin-stimulated glucose uptake in red, oxidative muscle and adipocytes by: (1) disrupting insulin receptor mediated signal transduction and/or (2) impairing the ability of GLUT4 vesicles to dock and fuse with the plasma membrane. The effects of ethanol on early events in insulin signalling (insulin receptor substrate-1 phosphorylation and activation of phosphotidylinositol-3-kinase) which lead to translocation of GLUT4 will be measured. The applicants will also investigate the effects of ethanol on the intracellular distribution of GLUT4 protein after insulin stimulation, as well as the distribution of vesicular proteins involved in GLUT4 vesicle trafficking. Investigation of the mechanisms for ethanol-induced insulin resistance is critical for understanding the interaction between alcohol consumption and the development of NIDDM. Such an understanding will foster the development of strategies to either prevent or reverse the long-term effects of ethanol on glucose homeostasis.